Activation of P2X7 receptors in glial satellite cells reduces pain through downregulation of P2X3 receptors in nociceptive neurons.
Purinergic ionotropic P2X7 receptors (P2X7Rs) are closely associated with excitotoxicity and nociception. Inhibition of P2X7R activation has been considered as a potentially useful strategy to improve recovery from spinal cord injury and reduce inflammatory damage to trauma. The physiological functions of P2X7Rs, however, are poorly understood, even though such information is essential for making the P2X7R an effective therapeutic target. We show here that P2X7Rs in satellite cells of dorsal root ganglia tonically inhibit the expression of P2X3Rs in neurons. Reducing P2X7R expression using siRNA or blocking P2X7R activity by antagonists elicits P2X3R up-regulation, increases the activity of sensory neurons responding to painful stimuli, and evokes abnormal nociceptive behaviors in rats. Thus, contrary to the notion that P2X7R activation is cytotoxic, P2X7Rs in satellite cells play a crucial role in maintaining proper P2X3R expression in dorsal root ganglia. Studying the mechanism underlying the P2X7R-P2X3R control, we demonstrate that activation of P2X7Rs evokes ATP release from satellite cells. ATP in turn stimulates P2Y1 receptors in neurons. P2Y1 receptor activation appears to be necessary and sufficient for the inhibitory control of P2X3R expression. We further determine the roles of the P2X7R-P2Y1-P2X3R inhibitory control under injurious conditions. Activation of the inhibitory control effectively prevents the development of allodynia and increases the potency of systemically administered P2X7R agonists in inflamed rats. Thus, direct blocking P2X7Rs, as proposed before, may not be the best strategy for reducing pain or lessening neuronal degeneration because it also disrupts the protective function of P2X7Rs.
Chen
Yong
Y
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555-1069, USA.
Zhang
Xiaofei
X
Wang
Congying
C
Li
Guangwen
G
Gu
Yanping
Y
Huang
Li-Yen Mae
LY
D000818:Animals; D015536:Down-Regulation / Q000235:genetics*; D005727:Ganglia, Spinal; D008297:Male; D009457:Neuroglia / Q000378:metabolism*; D010146:Pain; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D058477:Receptors, Purinergic P2X3; D058486:Receptors, Purinergic P2X7; D027161:Satellite Cells, Perineuronal / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000737:chemistry
D018048:Receptors, Purinergic P2; D058477:Receptors, Purinergic P2X3; D058486:Receptors, Purinergic P2X7